The role of maternal neutralizing antibodies (NAbs) in determining whether an infant becomes infected during Mother to Child Transmission (MTCT) of HIV-1 is unclear. Higher levels of both autologous and heterologous NAbs are associated with non-transmission, and NAb-resistant isolates are transmitted. This topic is timely and important, as there is increasing interest in testing vaccines or immunotherapies during the early breastfeeding period, when postpartum transmission risk is highest and drug therapy can select resistant isolates. Would the augmentation of the passively transferred maternal NAbs with human monoclonals (mAbs) be effective in this setting? To address some of these questions experimentally outside the clinic, we have established a perinatal SHIV transmission model in M. nemestrina. In this model, we have observed durable plasma virus control in newborn macaques infected orally with SHIV- SF162P3 in the presence of sub-sterilizing levels of IgG that neutralized the challenge virus. We have shown that passively transferred NAbs can accelerate de novo anti-SHIV NAbs, similar to experiments in the SIV model. In this renewal, we propose to shift the focus toward understanding the mechanisms behind these observations. In AIM 1, we plan to comprehensively evaluate the anti-SHIV T- and B-cell responses in SHIV-IgG-treated and control adult macaques for magnitude, timing, avidity, specificity, conformation-dependence, and breadth. In AIM 2, we plan to characterize the development of specific B cell responses in macaques with accelerated versus normal neutralizing responses by cloning antibody variable regions from individual antibody-secreting B cells (ASCs) and reconstructing them as human IgG1 antibodies. By this method, we can capture the diversity of the early IgG response and characterize the Env-specific mAbs for antiviral activity including neutralization and ADCVI. In AIM 3, we will test the effectiveness of new HIV Env-specific mAbs in complementing maternal SHIV-IgG as a more effective passive immunotherapy in newborns. We propose that these experiments will yield valuable information about the mechanisms of antibodies in controlling HIV in vivo and may inform potential immunotherapies to limit MTCT in the clinic. PUBLIC HEALTH RELEVANCE: Summary and rationale/health relevance of the proposed work The SHIV-macaque model provides advantages of a pathogenic infection with a virus bearing the HIV Envelope protein, the target of HIV-1 neutralizing antibodies. We established a perinatal SHIV transmission model in macaques and have shown that maternal neutralizing antibodies highly benefit the immune responses and the clinical outcome of the newborn. In this renewal, we propose to comprehensively analyze the antibodies and T cell responses that develop in the presence of maternally transferred IgG so that we can understand their mechanism of action. We will isolate human monoclonals that can neutralize HIV-1, and then test these in our nonhuman primate model as immunotherapies to control SHIV infection.